Nociceptin (the same substance as orphanin FQ) is a peptide composed of 17 amino acids and having a similar structure to that of opioid peptide. Nociceptin has an augmenting activity on reaction against noxious stimulae, an appetite stimulating activity, an activity for reducing a space learning ability, an antagonism against an analgesic action of classic opiate agonists, a dopamine release inhibitory action, a water diuresis action, a vasodilative action, a systemic blood pressure-lowering action and cell excitation inhibitory action, and it is considered to take part in controlling pain, appetite and memory, learning or emotional function through nociceptin receptor in the brain [refer to Nature, 1995, 377, 532; Society for Neuroscience, 1996, 22, 455; NeuroReport, 1997, 8, 423; Eur. J. Neuroscience, 1997, 9, 194; Neuroscience, 75, 1 and 333; and Life Sciences, 1997, 60, PL15 and PL141].
Further, it is known that morphine tolerance is reduced in knockout mice in which expression of nociceptin receptor is inhibited (Neuroscience Letters, 1997, 237, 136).
Heretofore known pharmacological activities of nociceptin or nociceptin receptor agonist from various reports include the following.    1) Administration of nociceptin was shown to have reduced reactivity to anxiety and stress (Proceedings of the National Academy of Sciences of the United States of America, 1997, 94, 14854–14858), which suggested nociceptin's having antianxiety or antidepressing action.    2) Nociceptin and nociceptin receptor agonist were shown to produce reduction of motor activity and sedation (Naunyn-Schmiedeberg's Archives of Pharmacology, 2001, 363, 161–165; Proceedings of the National Academy of Sciences of the United States of America, 2000, 97, 4938–4943). Nociceptin is also known to affect photosynchronization of biological clock (Journal of Neuroscience, 1999, 19, 2152–2160), which suggest its controlling role over sleep-and-waking cycle and circadian rhythm.    3) Nociceptin receptor agonist is known to show analgesia at spinal level (Tips, 1997, 18, 293–300). It was furthermore suggested to show little addictive tendency as highly active analgesic (Nature, 1995, 377, 476).    4) Nociceptin is known to inhibit airway contraction caused by substance P which induces airway contraction during inflammation such as asthuma or chronic airway obstruction (Journal of Pharmacology & Experimental Therapeutics, 1998, 285, 902–907), which suggests its effect to improve dyspenea induced by inflammatory airway contraction or antitussive effect.    5) Nociceptin is shown to increase cavernosal pressure at corpus cavernosum penis tissue to cause erection (American Journal of Physiology, 1997, 273, E214–E219), which suggests improvement of erectile dysfunction.    6) Nociceptin has accelerating action on motility of digestive tract (British Journal of Pharmacology, 2000, 130, 1639–1645), suggesting its ameliorating motility of digestive tract dysfunction such as hypokinesis of digestive tract.
Accordingly, compounds having nociceptin receptor agonist activities are presumed to act as analgesic, reliever from tolerance to narcotic analgesic represented by morphine; reliever from dependence on narcotic analgesic represented by morphine; analgesic enhancer; antiobestic; drug for ameliorating brain function; remedy for schizophrenia; drug for treating regressive neurodegenerative diseases represented by Parkinsonism and chorea; antianxiety agent or antidepressant; remedy for diabetes insipidus; remedy for polyuria; remedy for hypotension; anesthetic or anesthetic adminiculum; remedy for sleep disorders represented by insomnia including increased sleep latency, intermittent wakefulness and decreased sleep efficiency; remedy for circadian rhythm disorder such as jet lag; drug for improving erectile function; airway dilation during dyspenea such as asthma or antitussive; or as drug for ameliorating motility of digestive tract during hypokinesis of digestive tract.
On the other hand, nociceptin receptor agonists are disclosed, for example, in JP 2000-128879A or EP 963987A2, but they all are structurally different from 4-oxoimidazolidine-2-spiropiperidine derivatives of the present invention.
Also as compounds analogous of 4-oxoimidazolidine-2-spiropiperidine derivatives of the present invention, for example, WO 00/34280 pamphlet discloses nociceptin receptor inhibitor. However, the compounds shown in WO 00/34280 contain a —CH(R)—Cy (wherein Cy stands for an aliphatic carbocyclic group and R stands for hydrogen or lower alkyl) binding to nitrogen atom in a heterocyclic ring including piperidine ring, from which compounds of the present invention differ in the point that branched alkyl is bound to the nitrogen atom in piperidine ring. Furthermore, WO 00/34280 does not suggest selection of specific branched chain alkyl as the substituent to bind to the nitrogen atom in 4-oxoimidazolidine-2-spiropiperidine derivatives imparts nociceptin receptor agonist action to the compounds.
That is, compounds characterized in that piperidine is spiro-bound at 2-position of 4-oxoimidazoline ring and either a branched chain alkyl is bound to the nitrogen atom in the piperidine ring or an aliphatic carbocyclic group is directly bound to the nitrogen atom, are heretofore unknown. Nor it is known that 4-oxoimidazolidine-2-spiropiperidine derivatives having such a branched chain act specifically as nociceptin receptor agonist.
The objects of this invention are to provide the compounds having nociceptin receptor agonist action and also to provide analgesic, reliever from tolerance to narcotic analgesic represented by morphine; reliever from dependence on narcotic analgesic represented by morphine; analgesic enhancer; antiobestic; drug for ameliorating brain function; remedy for schizophrenia; drug for treating regressive neurodegenerative diseases represented by Parkinsonism and chorea; antianxiety agent or antidepressant; remedy for diabetes insipidus; remedy for polyuria; remedy for hypotension; anesthetic or anesthetic adminiculum; remedy for sleep disorders represented by insomnia including increased sleep latency, intermittent wakefulness and decreased sleep efficiency; remedy for circadian rhythm disorder such as jet lag; drug for improving erectile function; airway dilation during dyspenea such as asthma or antitussive; or as drug for ameliorating motility of digestive tract during hypokinesis of digestive tract, which act based on the pharmacological activity as nociceptin receptor agonist.